Background: Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%. Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%. Summary We are using functional genomics approach to determine the role of candidate genes, differentially expression by mRNA and microRNA expression profiling in thyroid cancer and adrenocortical carcinoma human tumor samples, in in vitro and in vivo models. The role of the candidate genes in regulating the hallmarks of malignant phenotype such as cellular proliferation, invasion and migration, and tumor angiogenesis is being tested using gene knockdown and knockin experiments to identify critical regulators and thus targets for therapy. We have completed a quantitative high throughput screening strategy for the identification of novel agents for thyroid cancer and adrenocortical carcinoma. In collaboration with the Chemistry group at the NIH Chemical Genomic Center, we screened 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of the compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. We have identified over 30 compounds with high confidence activity against thyroid cancer and adrenocortical carcinoma cell lines. We are currently validating the anticancer activity of the most potent compounds and plan to translate these findings into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma.